Tertiary-aminoalkyl 4-amino-2-benzyloxy-benzoates and debenzylation thereof



Patented Dec. 15, 1953 UNITED STATES PATENT OFFICE TERTIARY AMINOALKYL4-A1VIIN O- Z-BEN- ZYLOXY BEN ZOATES AND DEBENZYLA- TION THEREOF Raymond0. Clinton, North Greenbush, and Stanley C. Laskowski, Menands, N. Y.,assignonl to Sterling Drug, Inc., New York, N. Y., a corporation ofDelaware No Drawing. Original application June 17, 1950,

Serial No. 168,841. Divided and this application August 17; 1951, SerialNo. 242,421

20 Claims. (Cl. 260-2943) 1 This application relates totertiary-aminoalkyl esters of 4-amino-2-hydroxybenzoic acid, towater-soluble acid-addition salts thereof, and to the preparation ofthese new compounds. In

on different carbon atoms. Thus X includes such --CH2CH2CH2CH2,-CH2CH(CH2) CH2--, and the like. The lower aliphatic-like tertiary-aminoradical shown above as NRR comprehends lower dialkylamino radicals whereR and R are lower alkyl groups, alike or different, and each alkyl grouphaving preferably 1-6 carbon atoms, such dialkylamino radicals includingdimethylamino, diethylamino, ethylmethylamino, diisopropylamino,di-mbutylamino, di-n-hexylamino and the like. Further, the loweraliphatic-like tertiary-amino radical designated as NRR encompassesthose radicals where R and R' are joined directly or through an oxygenatom to form saturated N-heteromonocyclic radicals having -6 ring atoms,illustrated by examples such as l-piperidyl, Z-methyl 1 piperidyl,3-ethyl-1- piperidyl, 4-methyl-l-piperidyl, 2,6-dimethyl-lpiperidyl,l-pyrrolidyl,

Z-methyl-I pyrtolidyl. to

2 2,5-dimethyl-l-pyrrolidyl, the like.

The above basic esters are prepared by esteritying 4nitro-2-hydroxybenzoic acid to produce the tertiary-aminoalkyl4-nitro-2-hydroxybenzoate having the formula 4-morpholinyl, and

OH (IJOO-XNRR' where X and NRR' have the meanings given hereinabove, andreducing said basic 4-nitro-2- hydroxybenzoate to the correspondingtertiaryaminoalkyl 4-amino-2-hydroxybenzoate. A specific illustration ofthis procedure is the formation of 2-dimethylaminoethy14-amino-2-hydroxybenzoate by esterifying 4-nitro-2-hydroxybenzoic acidto produce 2-dimethylaminoethyl 4- nitro-2-hydroxybenzoate and reducingthe latter to form z -dimethylaminoethyl 4-amino-2- hydroxybenzoate. Wecarried out the esterification of 4-nitro-2-hydroxybenzoic acid toproduce the corresponding tertiary-aminoalkyl ester in various ways. Inone procedure, the 4-nitro-2- hydroxybenzoic acid was reacted with atertiaryaminoalkyl halide. In another procedure, a lower alkyl4-nitro-2-hydroxybenzoate was transesterified with atertiary-aminoalkanol. In still another procedure, the4-ni-tro-2-hydroxybenzoic acid was first treated with a haloalkanol toproduce a haloalkyl ester which was reacted with a secondary amine toyield the desired tertiaryaminoalk-yl ester. Thus, in the above specificillustration, Z-dimethylaminoethyl 4-nitro-2-hydroxybenzoate' isprepared by reacting 4-nitro-2- hydroxybenzoic acid withZ-dimethylaminoethyl chloride: by reacting methyl 4-nitro2-hydroxybenzoate with Z-dimethylaminoethanol; or by first reacting 4 nitro 2hydroxybenzoic acid with ethylene chlorohydrin and treating the re- 1suiting 2-chlor-oethyl 4nitro-2-hydroxybenzoate with dimethylamine.

The reduction of the tertiary-aminoalkyl 4i-nitro-2-hydroxybenzoates tothe corresponding -amiho-2-hydroxybenzoates was carried out both bychemical methods and by catalytic hydrogenation. Suitable chemicalreducing agents include iron and hydrochloric acid, ferrous sulfate andammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. Catalystssuitable when catalytic hydrogenation is used include Raney nickel,platinum, palladium, or other catalysts generally effective to catalyzehydrogenation of nitro groups to amino groups.

Our tertiary-aminoalkyl 4-amino-2-hydroxybenzoates employed as the freebases or as their salts with relatively non-toxic organic or inorganicacids. We found it convenient to isolate the basic esters as theirhydrochlorides oiphosphates. However, other acid-addition salts arewithin the scope of our invention. Such additional salts include thehydrobromides, sulfates, citrates, sulfamates, tartrates, succinates,acetates, benzoates, oleates, and the like.

Specific embodiments of our invention are illustrated in the followingparagraphs;

1. Tcrtiary-aminoalkyl 4-nz'tro-2-hyd1'oxybenzoates These basic esterswere prepared from -nitro- 2-hydroxybenzoic acid by the followingesterification variants: by the reaction of 4-nitro-2-hydroxybenzoicacid with a tertiary-aminoalkyl halide; by the reaction of a lower alkyli-nitro- 2-hydroxybenzoate with a tertiary-aminoalkanol or by thereaction of 4-nitro-2-hydroxybenzoic acid with a haloalkanol followed bytreatment of the resulting haloalkyl esterwith a secondary amine.

The first variant is illustrated by the following preparation ofZ-diethylaminoethyl 4-nitro-2- hydroxybenzoate hydrochloride: To astirred, refluxing solution of 137.5 g. of 4-nitro-2-hydroxybenzoic acidin 800 ml. of isopropanol was added dropwise 110 g. of2-diethylaminoethyl chloride during the course of one and one-halfhours. The resulting heterogeneous mixture was stirred and refluxed foran additional seven hours, cooled, and the dense white precipitate wascollected. The filtrate was evaporated to dryness in vacuo and theresulting residue was triturated with acetone. The acetone-insolublematerial was combined with the original precipitate and the material wasrecrystallized several times from ethanol in the presence of a smallamount of anhydrous hydrogen chloride. There was obtained 161.4 g.(67.7%) of Z-diethylaminoethyl 4-nitro-2-hydroxybenzoate hydrochloride,M. P. 1795-1801? C. (corn), crystallizing in white needles.

The second procedure of reacting a lower alkyl -nitro-2-hydroxybenzoatewith a tertiaryaminoalkanol is illustrated by the following preparationof 3-(2- nethyl-l-piperidyl)propyl l-nitro-2-hydroxybenzoatehydrochloride: A mixture of 84.5 g. of ethyl 2-hydroxy-4-nitrobenzoate,70.8 g. of 3-(2-methyl-l-piperidyl)propanol, 700 ml. of dry toluene and200 mg. of sodium methoxide was slowly distilled through an efficientfractionating column. The evolution of ethanol was slow, requiringforty-eight hours for completion. The residue was evaporated in vacuoand the resulting viscous oil was dissolved in ethyl acetate and treatedwith an excess of ethereal hydrogen chloride. The resulting thick heavyoil was separated by decantation and dissolved in dry acetone. Onscratching and cooling this solution a dense white precipitate appeared.Several recrystallizations from isopropanol gave 55.7 g. (39%) of3-(2-methyl-1-piperidyl)propyl are therapeutically active Whether 44-nitro-2-hydroxybenzoate hydrochloride, crystallizing in needles, M. P.173.0l73.8 C. (corn).

The third variant for preparing the tertiaryaminoalkyl4-nitro-2hydroxybenzoates is illustrated as follows: A mixture of onemole of 4- nitro-Z-hydroxybenzoic acid and three moles of ethylenechlorohydrin was heated to reflux and dry hydrogen chloride was passedinto the reaction mixture for eight hours. The excess ethylenechlorohydrin was removed by distilling in vacuo and the residue whencrystallized from absolute ethanol yielded 2-chloroethyl 4-nitro-2-hydroxybenzoate, M. P. 87.4-88.4" C. (corn). The corresponding2-bromoethyl ester, M. P. 74.774.9 C. (corn), resulted when ethylenebromohydrin was used in place of ethylene chlorohydrin. A mixture of onemole of 2-chloroethyl (or Z-bromoethyl) 4-nitro-2-hydroxybenzoate andtwo moles of diethylamine and 1500 ml. of toluene was refluxed fortwenty-four hours. After removal of the solvent by distilling in vacuo,the residue was dissolved in hydrochloric acid, the acidic solution wastreated with -decolorizing charcoal and filtered. The filtrate was madealkaline with potassium carbonate and the mixture was extracted withethyl acetate. After removal of the ethyl acetate by distilling invacuo, the residue was dissolved in absolute ethanol and the alcoholicsolution was treated with excess hydrogen chloride in ether. Addition ofexcess ether precipitated the basic ester salt, Z-diethylaminoethyl4-nitro-2-hydroxy-benzoate hydrochloride, which was recrystallized fromisopropanol.

Other tertiary-aminoalkyl 4-nitro-2-hydrcxybenzoate hydrochloridesprepared according to the foregoing procedures include those given inTable A.

TABLE A Additional tertiary-aminoalkyl 4-nitro-2-hydroxybenzoatehydrochlorides which can be prepared according to the above proceduresinclude the following: 4-dimethy1aminobutyl 4-nitro-2- hydroxybenzoatehydrochloride; 3 dimethylamino-2-propyl 4-nitro-2-hydroxybenzoatehydrochloride; Z-di-n-butylaminoethyl 4-nitro-2- hydroxybenzoatehydrochloride; 2 (1 pyrrolidyl)ethyl 4-nitro-2-hydroxybenzoatehydrochloride; 3- (2-methyl-l-pyrrolidyl) propyl 4-nitro-2-hydroxybenzoate hydrochloride; and 2-(2,5-di- 4nitro-2-hydroXY- DIIO2 2.Tertiary-aminoalkyl 4-amino-2-hyclroxw benzoates These esters areprepared by reducing the hereinabove described tertiary-aminoalkyl 4-nitro 2 hydroxybenzoates. This reduction is carried out either bychemical means or by cat alytic hydrogenation methods.

Exemplary of the chemical method is the following preparation of2(2,6-dimethyl-1-plperidyl) ethyl 4 amino 2 hydroxybenzoate: To astirred boiling mixture of 90 g. of iron powder. 200 ml. of water, 300ml. of ethanol and 1 ml. or concentrated hydrochloric acid was graduallyadded in portions 80.7 g. of 2-(2,6-dimethyl-l piperidyDethyl2-hydroxy-4-nitrobenzoate hydrochloride. Each addition. produced anexothermic reaction. When the addition had been completed, the mixturewas. stirred at the boiling, point for twenty minutes. While continuingstirring and heating, 30 to 40 g. of solid sodium bicarbonate wascautiously added. and the resulting mixture was stirred and heated anaddi-- tional ten minutes. The mixture was filtered hot and the filtercake washed Well with hot ethanol. The combined filtrates wereconcentrated in vacuo until all ethanol was removed. The residualaqueous suspension of the crystalline base was cooled and filtered, andthe precipitate was washed well with cold water. The. precipitatecrystallized from n-heptane in. rosettes of beautiful long slenderneedles of 2-(2,6-dimethyl-l-piperidyl)-ethyl -amino-z-hydroxybenzoate,M. P. l1l.011l.6 C. (corn). The phosphate of this basic ester wasprepared from mole equivalents of base and phosphoric acid (H3PO4) inabsolute ethanol and recrystallized by dissolving in a minimum amount ofhot water, filtering and slowly diluting with hot absolute ethanol. Theresulting salt, 2-(2,6-dimethyl-lpiperidyl) ethyl 4 amino 2hydroxybenzoate phosphate, melts at 19737-2000 C. tcorr.)

A specific illustration of the catalytic hydrogenation method ofpreparing. our tertiaryaminoalkyl 4-amino-2-hydroxybenzoates is thefollowing synthesis of 3-(l-piperidyllpropyl 4.-amino-Z-hydroxybenzoate: A mixture of 10.0 g. of 3-(1-piperidyl)propyl4-nitro-2-hydroxybenzoate hydrochloride, 500 mg. of platinum oxide and150 m1. of 50% aqueous ethanol was hydrogenated in a Parr-Burgesshydrogenatorat 25- l5 C. and. 20-50 lbs. pressure. The theoreticalamount of hydrogen was absorbed in fifteen to twenty minutes. Themixture was filtered and evaporated to dryness in vacuo. The residualwhite solid was crystallized from ethanol to give a high yield of3-(1-piperidyl) propyl 4-amino-2- hydroxybenzoate hydrochloride, M. P.239.5- 240.2 C. (corn). The phosphate salt of this basic ester wasprepared as follows: 3-(1-piperidyl)propyl 4-amino-2-hydroxybenzoatehydrochloride, M. P. 239.5-240.2 0. (corn). The phosphate salt of thisbasic ester was prepared as follows: 3-(1-piperidyl)propyl 4-amino-2-hydroxybenzoate hydrochloride was converted to the crystalline base bytreatment of an aqueous solution thereof with an excess of sodiumcarbonate solution. The resulting base when treated with a one moleproportion of phosphoric acid in absolute alcohol solution readilyyielded 3- l-piperidyl) propyl 4-amino-2-hydroxybenzoate phosphate,forming rosettes of large blunt needles from ethanol, M. P. 204.7-205.0C. (dec.) (corn).

Other tertiary-aminoalkyl 4-amino-2-hydroxybenzoates prepared accordingto the above procedures include those given in Table B.

TABLE B I C 0 0(CH2)-NRR M. P./C. (corn) 1 NRR Base Phosphate N(CH3)21361-1372... 219. 7-220. 0 N(CzH5)z oil K 154. 0-154. 8 N 051110790-8015.. 0 223. 5-223. 8 NCsHn 6Q.0-62.0 203. 5-204. 0 N(CH3)2 oil e209. 6-210. 7 N(CH3)2 111.6-113 2 l 203. 2-204. 2 N GaH 201. 0-201. 5NC4HsO 64 265.(i 200. 7-201. 2 NOqHsO I46.4 185. 2-186. 7 N(CgH )2 oil212. 3

e With decomposition.

-Monohydroclriloride melts at 2250-2255 0. (corn).

8 Monohydrochloride. s lzgrystalhzed from dilute ethanol as themonohydrate. M. P.

Additional tertiary-aminoalkyl 4-amino-2-hydroxybenzoates which can beprepared according to the above procedures include the following:4-dimethylaminobutyl 4-amino-2-hydroxybenzoate; Z-di-n-butylaminoethyl4-amino-2-hydroxybenzoate; 2-(l-pyrrolidyl) ethyl 4-amino-2-hydroxybenzoate 3-(Z-methyl-l-pyrrolidyl) propyl4-amino-2-hydroxybenzoate; and 2-(2,5-dimethyl-l-pyrrolidyl) ethyl 4amino-Z-hyd'roxybenzoate.

The foregoing tertiary-aminoalkyl 4-amino-2- hydroxybenzoates are alsoconveniently prepared from 4-nitro-2-hydroxybenzoic acid or its loweralkyl esters through the 2-benzyloxy derivatives according to the stepsillustrated in the following' equations, wherein R" is a. lower alkylgroup *2 and X and NRR' have the meanings given hereinabove:

1102 BITO:

OH O CHzCaHs I II Thus, 4-nitro-2-benzyloxybenzolc acid (B) is preparedeither by benzylating 4-nitro-2-hydroxybenzoic acid (Step I) to form'benzyl 4-nitro-2- benzyloxybenzoate (A), which is saponified in Step IIto yield the desired 4-nitro-2-benzyloxybenzoic acid or by benzylating alower alkyl 4- nitro-2-hydroxybenzoate (Step I) to form a lower alkyl4-nitro-2-benzyloxybenzoate (A) which in Step II is saponified to thedesired acid (B). 4-nitro-2-benzyloxybenzoic acid is then esterified inStep III to produce the corresponding tertiary-aminoalkyl4-nitro-2-benzyloxybenzoate (C) which in Step IV is reduced to thecorresponding tertiary-aminoalkyl 4-amino-2-benzyloxybenzoate (D). Then,in Step V, the tertiaryaminoalkyl l-amino-Z-hydroxybenzoate (E) isproduced by catalytically debenzylating the basic4-amino-2-benzyloxybenzcate (D). Steps IV and V can be carried out inthe same reaction vessel without isolating compound D when the reductionis carried out catalytically, e. g., as with palladium on charcoal. As aspecific illustration of Steps III, IV and V, 4-nitro-2-benzyloxybenzoicacid is esterified to produce S-(Z-methyl-l-piperidyl) propyl-nitro-Z-benzyloxybenzoate which is then reduced to the corresponding3-(2-methyll-piperidyl) propyl i-amino-2-benzyloxybenzoate,'

iron and hydrochloric acid, ferrous sulfate, tin and hydrochloric acid,etc. We found iron and hydrochloric acid was to be preferred. Catalystssuitable when catalytic hydrogenation was employed include Raney nickel,platinum, palladium, etc. Reduction Step V was carried out by catalytichydrogenation, using preferably palladium, although platinum and Raneynickel can be used, the latter at higher temperatures and pressures.

The tertiaryaminoalky1 4-amino-2-benzyloxybenzoates are useful not onlyas intermediates in the preparation of the corresponding 2-hydroxyesters but also as local anesthetics in their own right. Thetertiary-aminoalkyl 4 amino 2- benzyloxybenzoates are therapeuticallyactive whether employed as the free bases or as their salts withrelatively non-toxic organic or inorganic acids. We found it convenientto isolate the basic Z-benzyloxy esters as their phosphates orhydrochlorides. However, other acid-addition salts are within the scopeof our invention. Such additional salts include the hydrobromides,sulfates, citrates, sulfamates, tartrates, succinates, acetates,benzoates, oleates, and the like.

Specific embodiments of our invention are 11- lustrated in the followingparagraphs.

3. 4-nitro-2-benzyloxybenzoic acid This acid was prepared from4-nitro-2-hydroxybenzoic acid through benzyl 4-nitro-2-benzyloxybenzoate and also from a lower alkyl 4-nitro-2-hydroxybenzoatethrough a lower alkyl 4-nitro-2-benzyloxybenzoate. Either preparationcan be carried out without the isolation of the intermediate ester.

Illustrative of the procedure using a lower alkyl4-nitro-2-hydroxybenzoate is the following where ethyl4-nitro-2-hydroxybenzoate is utilized: A mixture of 84.4 g. of ethyl4-nitro-2-hydroxybenzoate, 55.6 g. of benzyl chloride, 29.6 g. ofanhydrous sodium carbonate, 6.8 g. of potassium iodide, 400 ml. ofethanol and 2 ml. of water was refluxed and stirred for eight hours. Toisolate the ethyl 4-nitro-2-benzyloxybenzoate the mixture was filtered.hot and the insoluble material was washed with hot ethanol. The combinedfiltrates were concentrated to dryness in vacuo and the residue wasextracted exhaustively with hot n-hexane. When .cooled the extractsyielded 105.1 g. (87%) of ethyl 4-nitro-2-benzyloxybenzoatecrystallizing in long rods from n-hexane, M. P. 57.058.5 C. (corr.) Whenit was not desired to isolate the intermediate ethyl 4-nitro-2-benzyloxybenzoate, to the above hot mixture (after the reflux period ofeight hours) was added 400 ml. of water and g. of anhydrous sodiumcarbonate, and refluxing and stirring were continued for an additionalfive hours. lhe mixture was then filtered while hot and the precipitate,after washing well with hot ethanol, was discarded. The combinedfiltrates were concentrated in vacuo to remove the ethanol and theremaining aqueous solution was acidified to Congo red with hydrochloricacid. The resulting white precipitate was filtered off, washed well withWater and recrystallized twice from isopropanol, giving a yield of4-nitro2benzyloxybenzoate as short, thick, pale yellow needles, M. P.I'll-172 C. Comparable yields are obtained when other lower alkyl4-nitro-2-hydroxybenzoates, including the methyl, n-propyl and isobutylesters, are used in place of ethyl 4-nitro-2-hydroxybenzoate.

4. Tertiary-aminoalkyl 4-nitro-2-bnzyloxybenzoates In practicing ourinvention we prepared these basic esters by two procedures: one,byreactin'ga .4-nitro-2-benzyloxybenzoyl halide with atertiary-aminoalkanol; and the other, by-reacting a tertiary-aminoalkylhalide with 4-nitro-2-benzyloxybenzoic acid in an appropriate solvent.The former procedure is illustrated by the following synthesis of2-dimethylaminoethyl 4-nitro-2- benzyloxybenzoate: To a stirred coolmixture of 43.1 g. of pure pyridine, 64.5 g.'of pure thionyl chlorideand 1000 ml. of dry benzene, was added 148.9 g. of powdered, dry4-nitro-2-benzyloxybenzoic acid in four equal portions over a period oftwenty minutes. The heterogeneous mixture was then heated to 60 C. andallowed to stand for one and one-half hours at room temperature. Then,with cooling, there was added to this solution of4-nitro-2benzyloxybenzoyl chloride, 48.5 g. of redistilled2-dimethylaminoethanol. After cooling, the precipitated crystals werecollected and recrystallized from absolute ethanol-ethyl acetate,yielding 2-dimethylaminoethy1 i-nitroz-benzyloxybenzoate hydrochloride,M. P. 180.2 181.3 C. (corn). The free basic ester, 2-dimeth ylaminoethyl-nitro-2-benzyloxybenzoate, obtained by treatment of the abovehydrochloride with potassium carbonate, crystallized from dilute ethanolin pale yellow prisms, M. P. 60.0-60.7 C. (corn).

The above 4-nitro-2-benzyloxybenzoyl chloride is a yellow solid and maybe isolated before treatment with the tertiary-aminoalkanol.

The other procedure we utilized in preparing the tertiary-amino-alkyl4-nitro-2-benzyloxybenzoates, namely, the reaction of4-nitro-2-benzyloxybenzoic acid with a tertiary-aminoalkyl halide, isillustrated by the following preparation of 3- (1-piperidy1) propyl4-nitro-2-benzyloxybenzoate: A mixture of 54.6 g. of4-nitro-2-benzyloxybenzoic acid, 38.8 g. of 3-(1-piperidyl)propylchloride and 600 ml. of isopropanol was refiuxed for twenty hours. Theclear yellow-orange solution was then taken to dryness in vacuo and theresidue was taken up in water. The aqueous solution was made basic withpotassium carbonate and extracted with ethyl acetate. After drying theextract, the ethyl acetate was removed in vacuo leaving a crystallineresidue which when recrystallized from dilute ethanol, yielded 3-(1piperidyl) propyl 4 nitro 2 benzyloxybenzoate, M. P. 77.7-78.6" C.(corn). The hydrochloride of this basic ester, which was prepared bytreating a solution of the ester in ethanol with a solution of hydrogenchloride in ether, melts at 16l.4-162.5 C. (corn), when recrystallizedfrom dilute ethanol.

Additional tertiary-aminoalkyl 4-nitro-2-benzyloxybenzoates, in the formof their hydrochlorides, prepared according to the above describedprocedures are given in Table C.

l 0 TABLE 0 0 O Hnamino-2-propyl.

NOzHn=2=methyl-l-piperidyl. I

1 M. P. of free base is 57. 8-69.0 C. (com) a Free base is an oil.

Additional tertiary-aminoalkyl 4-nitro-2-benzyloxybenzoates which can beprepared according to the above procedures include the following:l-dimethylaminobutyl 4-nitro-2-benzyloxybenzoate; 2-di-n-butylaminoethyl4-nitro-2-benzyloxybenzoate; .2-(1-pyrrolidyl) ethyl 4 nitro 2-benzyloxybenzoate; 3- (2-methyll-pyrrolidyl) propyl4-nitro-2-benzyloxybenzoate; and 2-(2,5- dimethyl-l-pyrrolidyl) ethyl4-nitro-2-benzyloxy benzoate.

5. Tertiary-aminoalkyl 4-amz'n0 2 benzyloxybenzoates Illustrative of thepreferred procedure for preparing these basic esters is the followingpreparation of Z-dimethylaminoethyl 4-amino-2- benzyloxybenzoate: To avigorously stirred, boil- 1 9; mixture v 2f 10g. of powdered iron, 500ml. of ethanol,'800 ml. of water andl ml. of concentrated hydrochloricacid was gradually added 156.3 g. of 2-dimethylaminoethyl 4-nitro-2-benzyloxybenzoate hydrochloride. When the addition had been completed,the mixture was stirred at the boiling point for twenty minutes, treatedslowly with 40 g. of solid sodium bicarbonate, and stirred at theboiling point for an additional ten minutes. The mixturewas filteredwhile hot and the insoluble materialwas washed Well with hot ethanol.The ethanol was removedf rom the combined filtrates in vacuo and theresidual oil was taken up in ethyl acetate. After drying, anddecolorizing the solution with activated carbon, the ethyl acetate wasremoved in vacuo. The residual 2-dimethylaminoethy14-amin0-2-benzyloxybenzoate crystallized from a benzene-nhexane mixturein fiat white needles, M. P. 84.5-86.0 C. (corn). Fromthe base thefollowing salts were prepared by neutralization with the appropriateacid: 2-dimethylaminoethy1 4.- amino-Z-benzyloxybenzoate phosphate, M.P. 135.5-137.5 C. (corr.) and Z-dimethylaminoethyl4-amino-2-benzyloxybenzoate dihydrochloride, M. P. 169.6 C. (corr.)(dec.).

Alternatively, the nitro group can be reduced to the amino group withouteffecting debenzylationby catalytic hydrogenation of the base in ethanolsolution "using Raney nickel (but not palladium or platinum) ascatalyst, and at low pressures and temperature (25 lbs., 25 C.).

Additional tertiary-amincalkyl 4-amino-2- benzyloxybenzoatesin the formof their phosphates or hydrochlorides, prepared accordin to theaboveprocedure are given in Table D.

11, TABLE D benzyloxybenzoates which can be prepared according to theforegoing procedure include the following: -dimethylaminobutyl4-amino-2- benzyloxybenzoate; 2-di-n-butylaminoethyl 4- amino 2benzyloxybenzoate; 2-(l-pyrrolidyl) ethyl 4 amino 2 benzyloxybenzoate; 3(2- methyl-l-pyrrolidyl) propyl -amino 2 benzyloxybenzoate; and2-(2,5-dimethyl-l-pyrrolidyl) ethyl 4-amino-2-benzyloxybenzoate.

The above-described tertiary-aminoalkyl 4- amino-2-benzyloxybenzoatesare readily debenzylated by catalytic reduction to form thecorresponding tertiary-aminoalkyl 4-amino-2-hydroxybenzoates, which havebeen described hereinabove under Section 2. Hlustrative of thisprocedure is the following preparation of 3-(1- piperidyDpropyl4-amino-2-hydroxybenzoate: A mixture of 30 g. of 3-(1-piperidyl)propyl4- amino-2-benzyloxybenzoate, 25 ml. of concentrated hydrochloric acid,20 ml. of water, 100 ml. of 95% ethanol and 2 g. of a 7% palladiumchloride-on-oharcoal catalyst was shaken with hydrogen at 45 C. and 50lbs. pressure until the hydrogen absorption ceased (twenty to thirtyminutes). The mixture was filtered through a funnel precoated withdiatomaceous earth and the filter-pad was Washed with ethanol. Thecombined filtrates were neutralized with sodium bicarbonate and thealcohol was removed in vacuo. The residue crystallized on cooling,giving a quantitative yield of 3-(l-piperidyl)propyl 4-amino-2-hydrcxybenzoate, M. P. 57.5-58.5 C. (corr.). From the base canbe prepared the hydrochloride or the phosphate, identical with thosehereinabove described.

An alternative procedure is embodied in the direct conversion of2-dimethylaminoethyl 4- nitro-2-benzyloxybenzoate toZ-dimethylaminoethyl 4-amino-2-hydroxybenzoate: A mixture of 31.3 g. ofZ-dimethylaminoethyl 4-nitro-2-benzyloxybenzoate hydrochloride, 12.5 ml.of concentrated hydrochloric acid, 20 ml. of water, 100 ml. of ethanoland 4 g. of a 7% palladium chloride-on-charcoal catalyst was shaken withhydrogen, initially at room temperature and 50 lbs. pressure, andfinally at 45 C. and 50 lbs. pressure. The reduction proceded rapidly.The catalyst was removed by filtration and the resulting filtrate wasprocessed as. described above 12 to give 2-dimethylaminoethyl-amino-Z-hydroxybenzoate, M. P. 136137.2 C. (corn). From this base maybe prepared water-soluble salts identical with those hereinabovedescribed.

In the foregoing reductive debenzylating procedures the palladiumcatalyst, which we found to be preferable, can be replaced by othercatalysts such as platinum, Raney nickel, etc. Platinum is slightly lesseffective than palladium, and Raney nickel can be used only with highertemperatures and pressures.

Other tertiary-aminoalkyl 4-amino 2 hydroxybenzoates which can beprepared according to the above procedures are disclosed hereinaboveunder Section 2.

This application is a division of our copending application, Serial No.168,841, filed June 17, 1950.

We claim:

1. A member of the group consisting of basic ester having the formula 0OXN (lower alkyl):

where X is a lower alkylene radical having 2-4 carbon atoms.

3. A basic ester having the formula where X is a lower alkylene radicalhaving 2-4 carbon atoms and NRR' is a l-piperidyl radical.

4. 2 dimethylaminoethyl 4 amino 2 -benzyloxybenzoate.

5. 2 diethylaminoethyl 4 amino 2 benzyloxybenzoate.

6. 3 diethylaminopropyl 4 amino 2 benzyloxybenzoate.

7. A process of preparing a. basic ester having the formula where NRR isa radical selected from the group consisting of lower dialkylamino,l-piperidyl, (lower alkylatedl-l-piperidyl, l-pyrrolidyl, (loworalkylated)-lpyrrolidyl and 4-1norpholinyl and X is a lower alkyleneradical having 2-4 carbon atoms, which comprises catalyticallyhydrogenating in the presence of a member of the group consisting ofpalladium, platinum and nickel catalysts the corresponding Z-benzyloxybasic ester having the formula where Z is a member of the groupconsisting of N02 and NH2.

8. A process of preparing a basic ester having the formula NHz O O O X-N(lower alkylh where X is a lower alkylene radical having 2-4 carbonatoms, which comprises catalytically hydrogenating in the presence of apalladium catalyst the corresponding Z-benzyloxy basic ester having theformula 9. A process of preparing a basic ester having the formula ITTHzwhere X is a lower alkylene radical having 2-4 carbon atoms and NRR is al-piperidyl radical, which comprises catalytically hydrogenating in thepresence of a palladium catalyst the corresponding 2-benayloxy basicester having the formula 10. A process of preparing Z-dimethylaminoethyl4-amino-Z-hydroxy-benzoate which comprises catalytically hydrogenatingZ-dimethylaminoethyl 4-amino-2-benzyloxybenzoate in the presence of apalladium catalyst.

ooo-x-NRR' where X is a lower alkylene radical having 2-4 carbon atomsand NRR is a (lower alkylated)- l-piperidyl radical.

14. A basic ester having the formula IITH:

where X is a lower alkylene radical having 2-4 carbon atoms and NRR is a2-methyl-1-piperidyl radical.

15. 2-(2-methyl- 1 -piperidyl) ethyl 4-amino-2- benzyloxybenzoate.

16. 3 (1 piperidyDpropyl 4-amino-2-benzyloxy-benzoate.

1'7. A process of preparing a basic ester having the formula where X isa lower alkylene radical having 2-4 carbon atoms and NRR is a (loweralkylated) -1- piperidyl radical, which comprises catalyticallyhydrogenating in the presence of a palladium catalyst the corresponding2-benzyloxy basic ester having the formula IEIH:

18. A process of preparing a basic ester having the formula NHaGOO-X-NRR' where X is a lower alkylene radical having 2-4 carbon atomsand NRR is a Z-methyi-l-piperidyl radical, which comprises catalyticallyhydrogenating in the presence of a palladium cata- 15 16 lyst thecorresponding 2-benzy1oxy basic ester comprises catalyticallyhydrogenating 2 (2- having the formula methyl-l-piperidyl) ethyl 4amino-Z-benzyloxy- NH benzoate in the presence of a palladium catalyst.

20. A process of preparing 3-(1-piperidyD- 5 propyl4-amino-2-hydroxybenzoate which comprises catalytically hydrogenating3-(1-piperidyl) propyl 4-amino-2-benzy1oxybenzoate in the presence of apalladium catalyst. I RAYMOND O. CLINTON. COOQFNRR' 10 STANLEY c.LASKOWSKI.

19. A process of preparing 2-(2-methy1-1-piperidyl) ethyl4-amino-2-hydroxybenzoate which No references cited.

1. A MEMBER OF THE GROUP CONSISTING OF BASIC ESTER HAVING THE FORMULA